Time course of improvement in visual function and functional vision after treatment in two GUCY2D-LCA patients
Night vision restored in days after decades of congenital blindness
Paper
2022
iScience |
DOI
Background
Leber congenital amaurosis (LCA) caused by GUCY2D mutations leads to severe blindness due to defective retinal guanylyl cyclase 1 (RetGC1) and impaired cGMP production. This study reports two patients with GUCY2D-LCA who received AAV5-GUCY2D gene augmentation therapy. Before treatment, both had profound rod photoreceptor dysfunction. Within days post-therapy, dramatic improvements in rod-mediated vision occurred, reaching over 3 log units (1000-fold) by 3 months, nearing normal vision. Multiple measures confirmed efficacy localized to treated retinal regions. The rapid restoration after decades of dormancy suggests intact downstream pathways and highlights the potential of gene therapy for congenital blindness.
Key Findings
Two patients with GUCY2D-LCA received high-dose (3.3×10^11 vg/mL) AAV5-GUCY2D subretinal gene therapy. Both had severe rod vision loss at baseline but retained normal retinal structure. Within 8-12 days, rod sensitivity improved by ~2 log units, and by 3 months, improvements exceeded 3 log units (1000-fold), approaching healthy levels. Chromatic perimetry and microperimetry localized the gains to treated areas. Dark-adapted mobility thresholds improved by up to 5.6 log units, correlating with FST. Low-luminance visual acuity improved significantly in treated eyes. Pupillary light reflex thresholds improved objectively. Biochemical analysis of the patients' mutations (Arg588Trp and Trp708Arg) showed that mutant RetGC1 fails to bind GCAP1 and lacks enzymatic activity. The rapid recovery suggests that the phototransduction machinery remains intact despite decades of dysfunction, and gene augmentation can restore rod vision quickly.
Contribution
Creative Biogene provided the pRCCMV plasmid vector used to express wild-type and mutant RetGC1 in HEK293 cells for biochemical assays. This vector was crucial for demonstrating that the LCA-associated mutations (Arg588Trp and Trp708Arg) abolish GCAP1 binding and enzyme activity, thereby linking genotype to the patients' severe phenotype and supporting the rationale for gene therapy.
Leber congenital amaurosis (LCA) caused by GUCY2D mutations leads to severe blindness due to defective retinal guanylyl cyclase 1 (RetGC1) and impaired cGMP production. This study reports two patients with GUCY2D-LCA who received AAV5-GUCY2D gene augmentation therapy. Before treatment, both had profound rod photoreceptor dysfunction. Within days post-therapy, dramatic improvements in rod-mediated vision occurred, reaching over 3 log units (1000-fold) by 3 months, nearing normal vision. Multiple measures confirmed efficacy localized to treated retinal regions. The rapid restoration after decades of dormancy suggests intact downstream pathways and highlights the potential of gene therapy for congenital blindness.
Key Findings
Two patients with GUCY2D-LCA received high-dose (3.3×10^11 vg/mL) AAV5-GUCY2D subretinal gene therapy. Both had severe rod vision loss at baseline but retained normal retinal structure. Within 8-12 days, rod sensitivity improved by ~2 log units, and by 3 months, improvements exceeded 3 log units (1000-fold), approaching healthy levels. Chromatic perimetry and microperimetry localized the gains to treated areas. Dark-adapted mobility thresholds improved by up to 5.6 log units, correlating with FST. Low-luminance visual acuity improved significantly in treated eyes. Pupillary light reflex thresholds improved objectively. Biochemical analysis of the patients' mutations (Arg588Trp and Trp708Arg) showed that mutant RetGC1 fails to bind GCAP1 and lacks enzymatic activity. The rapid recovery suggests that the phototransduction machinery remains intact despite decades of dysfunction, and gene augmentation can restore rod vision quickly.
Contribution
Creative Biogene provided the pRCCMV plasmid vector used to express wild-type and mutant RetGC1 in HEK293 cells for biochemical assays. This vector was crucial for demonstrating that the LCA-associated mutations (Arg588Trp and Trp708Arg) abolish GCAP1 binding and enzyme activity, thereby linking genotype to the patients' severe phenotype and supporting the rationale for gene therapy.